mRNA expression of DOK1-6 in human breast cancer

Ghanem, Tamara; Bracken, James; Kasem, Abdul; Jiang, Wen Guo; Mokbel, Kefah

doi:10.5306/wjco.v5.i2.156

Cited by 18 publications

(17 citation statements)

References 56 publications

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“…A previous study revealed that the loss of DOK2 induces carboplatin resistance in ovarian cancer through the suppression of apoptosis [ 56 ]. Moreover, DOK2 was found to act as a potential tumor suppressor in human breast cancer [ 57 ]. Ohno et al [ 58 ] reported that the expression of the NLRP7 protein tend to be associated with poor prognosis in endometrial cancer tissues.…”

Section: Resultsmentioning

confidence: 99%

Functional consequences of somatic mutations in cancer using protein pocket-based prioritization approach

et al. 2014

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BackgroundRecently, a number of large-scale cancer genome sequencing projects have generated a large volume of somatic mutations; however, identifying the functional consequences and roles of somatic mutations in tumorigenesis remains a major challenge. Researchers have identified that protein pocket regions play critical roles in the interaction of proteins with small molecules, enzymes, and nucleic acid. As such, investigating the features of somatic mutations in protein pocket regions provides a promising approach to identifying new genotype-phenotype relationships in cancer.MethodsIn this study, we developed a protein pocket-based computational approach to uncover the functional consequences of somatic mutations in cancer. We mapped 1.2 million somatic mutations across 36 cancer types from the COSMIC database and The Cancer Genome Atlas (TCGA) onto the protein pocket regions of over 5,000 protein three-dimensional structures. We further integrated cancer cell line mutation profiles and drug pharmacological data from the Cancer Cell Line Encyclopedia (CCLE) onto protein pocket regions in order to identify putative biomarkers for anticancer drug responses.ResultsWe found that genes harboring protein pocket somatic mutations were significantly enriched in cancer driver genes. Furthermore, genes harboring pocket somatic mutations tended to be highly co-expressed in a co-expressed protein interaction network. Using a statistical framework, we identified four putative cancer genes (RWDD1, NCF1, PLEK, and VAV3), whose expression profiles were associated with overall poor survival rates in melanoma, lung, or colorectal cancer patients. Finally, genes harboring protein pocket mutations were more likely to be drug-sensitive or drug-resistant. In a case study, we illustrated that the BAX gene was associated with the sensitivity of three anticancer drugs (midostaurin, vinorelbine, and tipifarnib).ConclusionsThis study provides novel insights into the functional consequences of somatic mutations during tumorigenesis and for anticancer drug responses. The computational approach used might be beneficial to the study of somatic mutations in the era of cancer precision medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0081-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Functional consequences of somatic mutations in cancer using protein pocket-based prioritization approach

et al. 2014

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“…Lamkin, Chin, and Yen () identified that DOK1 / 2 proteins had a similar role in regulating myeloid cell proliferation and differentiation, suggesting functional similarities. Tumor suppressing roles of DOK1 / 2 have been reported in solid tissues and hematopoietic compartment in several studies (Berger et al, ; Coppin et al, ; Ghanem, Bracken, Kasem, Jiang, & Mokbel, ; Lee et al, , 2007; Niki et al, ; Yasuda et al, ). Genetic disruption of DOK1 / 2 in animal models and human tumor samples increased their susceptibility to leukemia development (Celis‐Gutierrez et al, ; Coppin et al, ; Mashima et al, , ; Niki et al, ; Yasuda et al, ).…”

Section: Discussionmentioning

confidence: 96%

Methylation‐associated DOK1 and DOK2 down‐regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia

Zhou

et al. 2018

Journal Cellular Physiology

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DOK-1 and DOK-2 (DOK1/2) are closely related members of downstream of tyrosine kinase (DOK) family genes, which are found to be frequently rearranged in several hematopoietic cancers. However, the clinical implications of DOK1/2 in acute myeloid leukemia (AML) remain largely unknown. To investigate the clinical significance, real-time quantitative PCR (RQ-PCR) was carried out to detect DOK1/2 expressions in 125 de novo AML patients and 28 healthy controls. Real-time quantitative methylation-specific PCR (RQ-MSP) and bisulfite sequencing PCR (BSP) were applied to detect DOK1/2 methylation level and density. DOK1/2 expressions were significantly down-regulated in AML patients. The promoters of DOK1/2 were highly hypermethylated and negatively correlated with DOK1/2 expressions in AML patients. In addition, we also confirmed that DOK1/2 expressions could be restored by DOK1/2 demethylation using 5-aza-2'-deoxycytidine in leukemia cell line THP-1. Survival analyses showed that low-expressed DOK1/2 were associated with markedly shorter overall survival and leukemia free survival in both whole-cohort AML and non-M3 AML patients. Multivariate analyses further revealed that DOK1/2 were act as independent prognostic factors in AML patients. These findings indicate that decreased DOK1/2 expressions associated with their promoter hypermethylations predict adverse prognosis in AML.

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“…Paradoxically, upon hematopoietic stress, Dok proteins oppose the quiescence of HSC (8,9,48,49). Dok1 and Dok2 dysregulations have been associated with several oncogenic processes (1,6,7,12,(50)(51)(52)(53)(54)(55)(56). Therefore, the impact of chemotherapeutic agents on HSCs may have to be considered to avoid resistance of leukemic stem cells and subsequent relapse.…”

Section: Discussionmentioning

confidence: 99%

Dok1 and Dok2 Proteins Regulate Cell Cycle in Hematopoietic Stem and Progenitor Cells

Coppin

Grandis

Pandolfi

et al. 2016

The Journal of Immunology

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Dok1 and Dok2 proteins play a crucial role in myeloid cell proliferation as demonstrated by Dok1 and Dok2 gene inactivation, which induces a myeloproliferative disease in aging mice. In this study, we show that Dok1/Dok2 deficiency affects myeloproliferation even at a young age. An increase in the cellularity of multipotent progenitors is observed in young Dok1/Dok2-deficient mice. This is associated with an increase in the cells undergoing cell cycle, which is restricted to myeloid committed progenitors. Furthermore, cellular stress triggered by 5-fluorouracil (5-FU) treatment potentiates the effects of the loss of Dok proteins on multipotent progenitor cell cycle. In addition, Dok1/Dok2 deficiency induces resistance to 5-FU–induced hematopoietic stem cell exhaustion. Taken together, these results demonstrate that Dok1 and Dok2 proteins are involved in the control of hematopoietic stem cell cycle regulation.

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mRNA expression of DOK1-6 in human breast cancer

Cited by 18 publications

References 56 publications

Functional consequences of somatic mutations in cancer using protein pocket-based prioritization approach

Functional consequences of somatic mutations in cancer using protein pocket-based prioritization approach

Methylation‐associated DOK1 and DOK2 down‐regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia

Dok1 and Dok2 Proteins Regulate Cell Cycle in Hematopoietic Stem and Progenitor Cells

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